Compounds and Their Use as PDE4 Activators

Abstract

The present invention relates to compounds of Formulas I to IV, their use as activators of long form cyclic nucleotide phosphodiesterase-4 (PDE4) enzymes (isoforms) and to these compounds for use in a method for the treatment or prevention of disorders requiring a reduction of second messenger responses mediated by cyclic 3′,5′-adenosine monophosphate (cAMP).

1 . A compound of Formula I 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or derivative thereof, wherein:
 one of X 1  and X 2  is N and the other is N or CR 3a , one of Y 1  and Y 2  is N and the other is C, and one of Z 1 , Z 2  and Z 3  is N or CR 3b  and the others are each CR 3b ; or 
 one of X 1  and X 2  is N and the other is NR 3c  or O, Y 1  and Y 2  are each C, and one of Z 1 , Z 2  and Z 3  is N or CR 3b  and the others are each CR 3b ; or 
 one of X 1  and X 2  is S and the other is N or CR 3a , Y 1  and Y 2  are each C, and one of Z 1 , Z 2  and Z 3  is N and the others are each CR 3b ; 
 R 1  is a 4- to 10-membered monocyclic, bridged or bicyclic ring containing at least 1 ring N heteroatom and optionally a ring O heteroatom, and wherein R 1  is optionally substituted with 1 or more R 4 ; 
 R 2  is 
 (v) (C5-7)cycloalkyl, fused to a 6-membered aromatic or heteroaromatic ring that contains 0, 1 or 2 ring N atoms; 
 (vi) a 5- to 7-membered non-aromatic heterocycle containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring that contains 0, 1 or 2 ring N atoms; 
 (vii) CH 2 Ar, where Ar is a 6-membered aromatic or heteroaromatic ring that contains 0, 1 or 2 ring N atoms; or 
 (viii) a (C3-8)alkyl group that may be straight chain, branched or cyclic, or a combination thereof; 
 and wherein R 2  is optionally substituted with 1 or more R 5 ; 
 each R 3a  is independently H or (C1-6)alkyl, the (C1-6)alkyl being optionally substituted by 1 or more halogen; 
 each R 3b  is independently H, (C1-6)alkyl, (C1-6)alkoxy, CN or halogen, the (C1-6)alkyl and (C1-6)alkoxy being optionally substituted by 1 or more halogen; 
 each R 3c  is independently H or (C1-6)alkyl, the (C1-6)alkyl being optionally substituted by 1 or more halogen; 
 each R 4  is independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl or —(C1-6)alkylene-(C1-6)alkoxy, the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl and —(C1-6)alkylene-(C1-6)alkoxy being optionally substituted with 1 or more substituents independently selected from halogen, OH and (C1-6)alkoxy; and 
 each R 5  is independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy or —(C1-6)alkylene-(C1-6)alkoxy, the (C1-6)alkyl and (C1-6)alkoxy being optionally substituted by 1 or more halogen or OH; 
 for use in the treatment or prevention of a disease or disorder that can be ameliorated by activation of long isoforms of PDE4 or a disease or disorder mediated by excessive intracellular cyclic AMP signalling. 
 
       
     
     
         2 . The compound, or a pharmaceutically acceptable salt or derivative thereof, for use of  claim 1 , wherein R 1  is a 5- to 6-membered saturated, monocyclic ring containing at least 1 ring N heteroatom and optionally a ring O heteroatom; a 5- to 6-membered aromatic, monocyclic ring containing 1 or 2 ring N heteroatoms; or a 7- to 8-membered saturated, bridged ring containing 1 or 2 ring N heteroatoms; a 9-membered saturated, bridged ring system containing 2 ring N heteroatoms and a ring O-heteroatom; or a 7- to 10-membered saturated, fused or spiro ring system containing 1 or 2 ring N heteroatoms; and wherein R 1  is optionally substituted with 1, 2 or 3 R 4 , optionally R 1  is a 7- to 8-membered saturated, bridged ring containing 1 or 2 ring N heteroatoms. 
     
     
         3 . The compound, or a pharmaceutically acceptable salt or derivative thereof, for use of  claim 1 or 2 , wherein R 1  is a 7- to 8-membered saturated, bridged ring containing 1 or 2 ring N heteroatoms, wherein at least 1 ring N heteroatom is not at the point of attachment of R 1 , and wherein R 1  is optionally substituted with 1 R 4 . 
     
     
         4 . The compound, or a pharmaceutically acceptable salt or derivative thereof, for use of  any preceding claim , wherein R 2  is:
 (i) (C5-7)cycloalkyl, fused to a 6-membered aromatic or heteroaromatic ring that contains 0, 1 or 2 ring N atoms, wherein the (C5-7)cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from OH, halogen, (C1-4)alkyl and (C1-4)alkoxy, the (C1-4)alkyl and (C1-4)alkoxy groups being optionally substituted with one or more fluoro, and the 6-membered aromatic or heteroaromatic ring is optionally substituted with 1 to 3 substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, CN and halogen, the (C1-4)alkyl and (C1-4)alkoxy groups being optionally substituted with one or more fluoro;   (ii) a 5- to 7-membered non-aromatic heterocycle containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring that contains 0, 1 or 2 ring N atoms, wherein the 5- to 7-membered non-aromatic heterocycle is optionally substituted with 1 to 3 substituents on one or more ring carbon atoms independently selected from OH, halogen, (C1-4)alkyl and (C1-4)alkoxy, the (C1-4)alkyl and (C1-4)alkoxy groups being optionally substituted with one or more fluoro, and the 6-membered aromatic or heteroaromatic ring is optionally substituted with 1 to 3 substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, CN and halogen, the (C1-4)alkyl and (C1-4)alkoxy groups being optionally substituted with one or more fluoro;   (iii) CH 2 Ar, wherein the Ar is optionally substituted with 1 to 3 substituents selected from halogen, CN, (C1-4)alkyl, (C1-4)alkoxy and the CH 2  is optionally substituted with (C1-4)alkyl the (C1-4)alkyl group being optionally substituted with OH or (C1-4)alkyloxy; or   (iv) a (C3-8)alkyl group that may be straight chain, branched or cyclic or a combination thereof, optionally substituted with 1 or more halogen, (C1-4)alkoxy or OH.   
     
     
         5 . The compound, or a pharmaceutically acceptable salt or derivative thereof, for use of  any preceding claim , wherein R 2  is:
 (i) (C5-6)cycloalkyl, optionally fused to a phenyl ring;   (ii) a 5- to 6-membered non-aromatic heterocycle containing one ring O heteroatom, optionally fused to a phenyl ring;   
       wherein R 2  is optionally substituted with 1 or more R 5 . 
     
     
         6 . The compound, or a pharmaceutically acceptable salt or derivative thereof, for use of  any preceding claim , wherein R 2  is a group of formula 
       
         
           
           
               
               
           
         
         wherein A is O or CH 2 ; p is 1, 2 or 3; Ph is an optionally present, fused phenyl ring, and wherein R 2  is optionally substituted with 1 or more R 5 ; optionally wherein A is O or C(R 5 ) 2  (for example, CF 2 ). 
       
     
     
         7 . The compound, or a pharmaceutically acceptable salt or derivative thereof, for use of  any preceding claim , wherein:
 a) each R 3a  is independently —H or CH 3 ;   b) each R 3b  is independently —H, —CH 3 , —OCH 3 , halo, CN or cyclopropyl; and/or   c) each R 3c  is independently —H or CH 3 .   
     
     
         8 . The compound, or a pharmaceutically acceptable salt or derivative thereof, for use of  any preceding claim , wherein 1 or 2 (preferably 1) of R 3a , R 3b  and R 3c  is as defined in any of  claims 1 or 7  and the others where present are each —H. 
     
     
         9 . The compound, or a pharmaceutically acceptable salt or derivative thereof, for use of  any preceding claim , wherein the bicyclic heteroaromatic ring system containing X 1 , X 2 , Y 1 , Y 2 , Z 1 , Z 2  and Z 3  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         10 . The compound, or a pharmaceutically acceptable salt or derivative thereof, for use of  any preceding claim , wherein one of X 1  and X 2  is N and the other is N or CR 3a , one of Y 1  and Y 2  is N and the other is C, and one of Z 1 , Z 2  and Z 3  is N or CR 3b  and the others are each CR 3b . 
     
     
         11 . The compound, or a pharmaceutically acceptable salt or derivative thereof, for use of any of  claims 1-9 , wherein one of X 1  and X 2  is S and the other is N or CR 3a , Y 1  and Y 2  are each C, and one of Z 1 , Z 2  and Z 3  is N and the others are each CR 3b . 
     
     
         12 . The compound, or a pharmaceutically acceptable salt or derivative thereof, for use of  any preceding claim , wherein
 R 1  is a 6-membered saturated   monocyclic ring containing 1 or 2 ring N heteroatoms, wherein at least 1 ring N heteroatom is not at the point of attachment of R 1 , or a 7- to 8-membered saturated, bridged ring system containing 2 ring N heteroatoms, and wherein R 1  is optionally substituted with 1 R 4 ;   R 2  is   (i) (C5-6)cycloalkyl, optionally fused to a phenyl ring; or   (ii) a 5- to 6-membered non-aromatic heterocycle containing one ring O heteroatom, optionally fused to a phenyl ring;   and wherein R 2  is optionally substituted with 1 or more R 5 ;   R 3a , R 3b  and R 3c , where present, are each independently H or methyl (optionally wherein 0 or 1 of R 3a , R 3b  and R 3c  is methyl and the others are H);   R 4 , where present, is (C1-6)alkyl optionally substituted with OH; and   R 5 , where present, is OH.   
     
     
         13 . A compound of Formula II 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or derivative thereof, wherein:
 one of X 1  and X 2  is N and the other is N or CR 3a , one of Y 1  and Y 2  is N and the other is C, and one of Z 1 , Z 2  and Z 3  is N or CR 3b  and the others are each CR 3b ; or 
 one of X 1  and X 2  is S and the other is N or CR 3a , Y 1  and Y 2  are each C, and one of Z 1 , Z 2  and Z 3  is N and the others are each CR 3b ; 
 R 1a  is a 4- to 10-membered non-aromatic ring that can be monocyclic, bridged or bicyclic containing at least 1 ring N heteroatom and optionally a ring O heteroatom, wherein at least 1 ring N heteroatom is not at the point of attachment of R 1a , and wherein R 1a  is optionally substituted with 1 or more R 4 ; 
 R 2  is 
 (v) (C5-7)cycloalkyl, fused to a 6-membered aromatic or heteroaromatic ring that contains 0, 1 or 2 ring N atoms; 
 (vi) a 5- to 7-membered non-aromatic heterocycle containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring that contains 0, 1 or 2 ring N atoms; 
 (vii) CH 2 Ar, where Ar is a 6-membered aromatic or heteroaromatic ring that contains 0, 1 or 2 ring N atoms; or 
 (viii) a (C3-8)alkyl group that may be straight chain, branched or cyclic, or a combination thereof; 
 and wherein R 2  is optionally substituted with 1 or more R 5 ; 
 each R 3a  is independently H or (C1-6)alkyl, the (C1-6)alkyl being optionally substituted by 1 or more halogen; 
 each R 3b  is independently H, (C1-6)alkyl, (C1-6)alkoxy, CN or halogen, the (C1-6)alkyl and (C1-6)alkoxy being optionally substituted by 1 or more halogen; 
 each R 4  is independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl or —(C1-6)alkylene-(C1-6)alkoxy, the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl and —(C1-6)alkylene-(C1-6)alkoxy being optionally substituted with 1 or more substituents independently selected from halogen, OH and (C1-6)alkoxy; and 
 each R 5  is independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy or —(C1-6)alkylene-(C1-6)alkoxy, the (C1-6)alkyl and (C1-6)alkoxy being optionally substituted by 1 or more halogen or OH. 
 
       
     
     
         14 . The compound or a pharmaceutically acceptable salt or derivative thereof of  claim 13 , wherein:
 a) each R 4  is independently halogen, CN, OH, (C1-2)alkyl, (C1-6)alkoxy or —(C1-6)alkylene-(C1-6)alkoxy, the (C1-2)alkyl, (C1-6)alkoxy and —(C1-6)alkylene-(C1-6)alkoxy being optionally substituted with 1 or more substituents independently selected from halogen, OH and (C1-6)alkoxy; and/or   b) R 2  is (C5-7)cycloalkyl, fused to a 6-membered aromatic or heteroaromatic ring that contains 0, 1 or 2 ring N atoms; a 5- to 7-membered non-aromatic heterocycle containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring that contains 0, 1 or 2 ring N atoms; or CH 2 Ar, where Ar is a 6-membered aromatic or heteroaromatic ring that contains 0, 1 or 2 ring N atoms; and wherein R 2  is optionally substituted with 1 or more R 5 .   
     
     
         15 . The compound or a pharmaceutically acceptable salt or derivative thereof of  claim 13 or 14 , wherein R 1a  is a 5- to 6-membered saturated, monocyclic ring containing at least 1 ring N heteroatom and optionally a ring O heteroatom; or a 7- to 8-membered saturated, bridged ring containing 1 or 2 ring N heteroatoms; a 9-membered saturated, bridged ring system containing 2 ring N heteroatoms and a ring O-heteroatom; or a 7- to 10-membered saturated, fused or spiro ring system containing 1 or 2 ring N heteroatoms; and wherein R 1a  is optionally substituted with 1, 2 or 3 R 4 . 
     
     
         16 . The compound, or a pharmaceutically acceptable salt or derivative thereof, of any of  claims 13-15 , wherein R 1a  is a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms or a 7- to 8-membered saturated, bridged ring system containing 2 ring N heteroatoms, wherein R 1a  is optionally substituted with 1 R 4 , optionally wherein R 1a  is a 7- to 8-membered saturated, bridged ring system containing 2 ring N heteroatoms, wherein R 1a  is optionally substituted with 1 R 4 . 
     
     
         17 . The compound, or a pharmaceutically acceptable salt or derivative thereof, of any of  claims 13-16 , wherein R 2  is:
 (i) (C5-7)cycloalkyl, fused to a 6-membered aromatic or heteroaromatic ring that contains 0, 1 or 2 ring N atoms, wherein the (C5-7)cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from OH, halogen, (C1-4)alkyl, and (C1-4)alkoxy, the (C1-4)alkyl and (C1-4)alkoxy groups being optionally substituted with one or more fluoro, and the 6-membered aromatic or heteroaromatic ring is optionally substituted with 1 to 3 substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, CN and halogen, the (C1-4)alkyl and (C1-4)alkoxy groups being optionally substituted with one or more fluoro;   (ii) a 5- to 7-membered non-aromatic heterocycle containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring that contains 0, 1 or 2 ring N atoms, wherein the 5- to 7-membered heterocycle is optionally substituted with 1 to 3 substituents on one or more ring carbon atoms independently selected from OH, halogen, (C1-4)alkyl, (C1-4)alkoxy, the (C1-4)alkyl and (C1-4)alkoxy groups being optionally substituted with one or more fluoro, and the 6-membered aromatic or heteroaromatic ring is optionally substituted with 1 to 3 substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, CN and halogen, the (C1-4)alkyl and (C1-4)alkoxy groups being optionally substituted with one or more fluoro;   (iii) CH 2 Ar, wherein Ar is optionally substituted with 1 to 3 substituents selected from halogen, CN, (C1-4)alkyl, (C1-4)alkoxy and the CH 2  is optionally substituted with (C1-4)alkyl the (C1-4)alkyl group being optionally substituted with OH or (C1-4)alkyloxy; or   (iv) a (C3-8)alkyl group that may be straight chain, branched or cyclic or a combination thereof, optionally substituted with 1 or more halogen, OH or (C1-4)alkoxy.   
     
     
         18 . The compound, or a pharmaceutically acceptable salt or derivative thereof, of any of  claims 13-17 , wherein R 2  is:
 (i) (C5-6)cycloalkyl, optionally fused to a phenyl ring;   (ii) a 5- to 6-membered non-aromatic heterocycle containing one ring O heteroatom, optionally fused to a phenyl ring; and   
       wherein R 2  is optionally substituted with 1 or more R 5 . 
     
     
         19 . The compound, or a pharmaceutically acceptable salt or derivative thereof, of any of  claims 13-18 , wherein R 2  is a group of formula 
       
         
           
           
               
               
           
         
         wherein A is O or CH 2 ; p is 1, 2 or 3; Ph is an optionally present, fused phenyl ring, and wherein R 2  is optionally substituted with 1 or more R 5 ; optionally wherein A is O or C(R 5 ) 2  (for example, CF 2 ). 
       
     
     
         20 . The compound, or a pharmaceutically acceptable salt or derivative thereof, of any of  claims 13-19 , wherein
 R 1a  is a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, wherein at least 1 ring N heteroatom is not at the point of attachment of R 1a , or a 7- to 8-membered saturated, bridged ring system containing 2 ring N heteroatoms, and wherein R 1a  is optionally substituted with 1 R 4 ;   R 2  is   (i) (C5-6)cycloalkyl, optionally fused to a phenyl ring; or   (ii) a 5- to 6-membered non-aromatic heterocycle containing one ring O heteroatom, optionally fused to a phenyl ring;   and wherein R 2  is optionally substituted with 1 R 5 ;   R 3a  and R 3b , where present, are each independently H or methyl (optionally wherein 0 or 1 of R 3a  and R 3b  is methyl and the others are H);   R 4 , where present, is (C1-6)alkyl optionally substituted with OH; and   R 5 , where present, is OH.   
     
     
         21 . A compound of Formula III 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or derivative thereof, wherein:
 one of X 1  and X 2  is N and the other is N or CR 3a , one of Y 1  and Y 2  is N and the other is C, and one of Z 1 , Z 2  and Z 3  is N or CR 3b  and the others are each CR 3b ; or 
 one of X 1  and X 2  is S and the other is N or CR 3a , Y 1  and Y 2  are each C, and one of Z 1 , Z 2  and Z 3  is N and the others are each CR 3b ; 
 R 1  is a 4- to 10-membered monocyclic, bridged or bicyclic ring containing at least 1 ring N heteroatom and optionally a ring O heteroatom, and wherein R 1  is optionally substituted with 1 or more R 4 ; 
 R 2a  is 
 (iii) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring that contains 0, 1 or 2 ring N atoms; 
 
         (35) a 5- to 7-membered non-aromatic heterocycle containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring that contains 0, 1 or 2 ring N atoms; or
 (iv) a (C5-6)cycloalkyl group; 
 and wherein R 2a  is optionally substituted with 1 or more R 5 ; 
 each R 3a  is independently H or (C1-6)alkyl, the (C1-6)alkyl being optionally substituted by 1 or more halogen; 
 each R 3b  is independently —H, (C1-6)alkyl, (C1-6)alkoxy, CN or halogen, the (C1-6)alkyl and (C1-6)alkoxy being optionally substituted by 1 or more halogen; 
 each R 4  is independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl or —(C1-6)alkylene-(C1-6)alkoxy, the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl and —(C1-6)alkylene-(C1-6)alkoxy being optionally substituted with 1 or more substituents independently selected from halogen, OH and (C1-6)alkoxy; and 
 each R 5  is independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy or —(C1-6)alkylene-(C1-6)alkoxy the (C1-6)alkyl and (C1-6)alkoxy being optionally substituted by 1 or more halogen or OH; and wherein when one of X 1  and X 2  is S and the other is N, Y 1  and Y 2  are each C, one of Z 1 , Z 2  and Z 3  is N and R 2a  is (iv) a (C5-6)cycloalkyl group, R 2a  is substituted by at least 2 R 5 . 
 
       
     
     
         22 . The compound, or a pharmaceutically acceptable salt or derivative thereof, of any of  claims 13-21 , wherein 1 or 2 (preferably 1) of R 3a  and R 3b  is a group other than H and the others, where present, are each H. 
     
     
         23 . A compound of Formula IV 
       
         
           
           
               
               
           
         
         or a pharmaceutically acceptable salt or derivative thereof, wherein:
 one of X 1  and X 2  is N and the other is N or CR 3a , one of Y 1  and Y 2  is N and the other is C, and one of Z 1 , Z 2  and Z 3  is N or CR 3b  and the others are each CR 3b ; or 
 one of X 1  and X 2  is S and the other is N or CR 3a , Y 1  and Y 2  are each C, and one of Z 1 , Z 2  and Z 3  is N and the others are each CR 3b ; 
 R 1  is a 4- to 10-membered monocyclic, bridged or bicyclic ring containing at least 1 ring N heteroatom and optionally a ring O heteroatom, and wherein R 1  is optionally substituted with 1 or more R 4 ; 
 R 2  is 
 (v) (C5-7)cycloalkyl, fused to a 6-membered aromatic or heteroaromatic ring that contains 0, 1 or 2 ring N atoms; 
 (vi) a 5- to 7-membered non-aromatic heterocycle containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring that contains 0, 1 or 2 ring N atoms; 
 (vii) CH 2 Ar, where Ar is a 6-membered aromatic or heteroaromatic ring that contains 0, 1 or 2 ring N atoms; or 
 (viii) a (C3-8)alkyl group that may be straight chain, branched or cyclic, or a combination thereof; 
 and wherein R 2  is optionally substituted with 1 or more R 5 ; 
 each R 3a  is independently H or (C1-6)alkyl, the (C1-6)alkyl being optionally substituted by 1 or more halogen; 
 each R 3b  is independently H, (C1-6)alkyl, (C1-6)alkoxy, CN or halogen, the (C1-6)alkyl and (C1-6)alkoxy being optionally substituted by 1 or more halogen, wherein at least 1 R 3b  is other than H; 
 each R 4  is independently halogen, CN, OH, (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl or —(C1-6)alkylene-(C1-6)alkoxy, the (C1-6)alkyl, (C1-6)alkoxy, (C3-7)cycloalkyl and (C1-6)alkylene-(C1-6)alkoxy being optionally substituted with 1 or more substituents independently selected from halogen, OH and (C1-6)alkoxy; and 
 each R 5  is independently halogen, OH, CN, (C1-6)alkyl, (C1-6)alkoxy or —(C1-6)alkylene-(C1-6)alkoxy the (C1-6)alkyl and (C1-6)alkoxy being optionally substituted by 1 or more halogen or OH. 
 
       
     
     
         24 . The compound, or a pharmaceutically acceptable salt or derivative thereof, of any of  claims 13-23 , wherein each R 3a  is independently —H or CH 3 , and/or each R 3b  is independently —H, —CH 3 , —OCH 3 , halo, CN or cyclopropyl. 
     
     
         25 . The compound, or a pharmaceutically acceptable salt or derivative thereof, of any of  claims 13-24 , wherein R 2  or R 2a  is:
 (i) (C5-7)cycloalkyl fused to a 6-membered aromatic or heteroaromatic ring that contains 0, 1 or 2 ring N atoms, wherein the (C5-7)cycloalkyl is optionally substituted with 1 to 3 substituents independently selected from OH, halogen, (C1-4)alkyl, (C1-4)alkoxy, the (C1-4)alkyl and (C1-4)alkoxy groups being optionally substituted with one or more fluoro, and the 6-membered aromatic or heteroaromatic ring is optionally substituted with 1 to 3 substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, CN and halogen, the (C1-4)alkyl and (C1-4)alkoxy groups being optionally substituted with one or more fluoro;   (ii) a 5- to 7-membered non-aromatic heterocycle containing one ring O heteroatom, optionally fused to a 6-membered aromatic or heteroaromatic ring that contains 0, 1 or 2 ring N atoms, wherein the 5- to 7-membered non-aromatic heterocycle is optionally substituted with 1 to 3 substituents on one or more ring carbon atoms independently selected from OH, halogen, (C1-4)alkyl, and (C1-4)alkoxy, the (C1-4)alkyl and (C1-4)alkoxy groups being optionally substituted with one or more fluoro, and the 6-membered aromatic or heteroaromatic ring is optionally substituted with 1 to 3 substituents independently selected from (C1-4)alkyl, (C1-4)alkoxy, CN and halogen, the (C1-4)alkyl and (C1-4)alkoxy groups being optionally substituted with one or more fluoro; or   (35) (iv) a (C5-6)cycloalkyl group, substituted by 2 or 3 substituents on one or more ring carbon atoms independently selected from OH, halogen, (C1-4)alkyl, (C1-4)alkoxy, the (C1-4)alkyl and (C1-4)alkoxy groups being optionally substituted with one or more fluoro, optionally wherein the (C5-6)cycloalkyl group is substituted by 2 halogen substituents (optionally on a single ring carbon atom).   
     
     
         26 . The compound, or a pharmaceutically acceptable salt or derivative thereof, of any of  claims 13-25 , wherein R 2  or R 2a  is:
 (i) (C5-6)cycloalkyl, optionally fused to a phenyl ring;   (ii) a 5- to 6-membered non-aromatic heterocycle containing one ring O heteroatom, optionally fused to a phenyl ring; or   wherein R 2  or R 2a  is optionally substituted, wherein when R 2a  is a (C5-6)cycloalkyl group not fused to a phenyl ring it is substituted by at least 2 R 5 .   
     
     
         27 . The compound, or a pharmaceutically acceptable salt or derivative thereof, of any of  claims 13-26 , wherein R 2  or R 2a  is a group of formula 
       
         
           
           
               
               
           
         
         wherein A is O or CH 2 ; p is 1, 2 or 3; Ph is an optionally present, fused phenyl ring, and wherein R 2  or R 2a  is optionally substituted with 1 or more R 5 ; and wherein when A is CH 2 , Ph is present or A is C(R 5 ) 2  (for example, CF 2 ). 
       
     
     
         28 . The compound, or a pharmaceutically acceptable salt or derivative thereof, of  claim 21 , wherein
 R 1  is a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, wherein at least 1 ring N heteroatom is not at the point of attachment of R 1 , or a 7- to 8-membered saturated, bridged ring system containing 2 ring N heteroatoms, and wherein R 1  is optionally substituted with 1 R 4 ;   R 2a  is   (i) (C5-6)cycloalkyl, optionally fused to a phenyl ring;   (ii) a 5- to 6-membered non-aromatic heterocycle containing one ring O heteroatom, optionally fused to a phenyl ring; or   and wherein R 2a  is optionally substituted with 1 or 2 R 5 , wherein when R 2a  is a (C5-6)cycloalkyl group, not fused to a phenyl ring, it is substituted by 2 R 5 ;   R 4 , where present, is (C1-6)alkyl optionally substituted with OH;   R 5 , where present, is OH.   
     
     
         29 . The compound or a pharmaceutically acceptable salt or derivative thereof, of any of  claims 21 to 28 , wherein R 1  is a 5- to 6-membered saturated, monocyclic ring containing at least 1 ring N heteroatom and optionally a ring O heteroatom; or a 7- to 8-membered saturated, bridged ring containing 1 or 2 ring N heteroatoms; a 9-membered saturated, bridged ring system containing 2 ring N heteroatoms and a ring O-heteroatom; or a 7- to 10-membered saturated, fused or spiro ring system containing 1 or 2 ring N heteroatoms; and wherein R 1  is optionally substituted with 1, 2 or 3 R 4 . 
     
     
         30 . The compound, or a pharmaceutically acceptable salt or derivative thereof, of any of  claims 21 to 29 , wherein R 1  is a 6-membered saturated monocyclic ring containing 1 or 2 ring N heteroatoms, wherein at least 1 ring N heteroatom is not at the point of attachment of R 1 , a 7- to 8-membered saturated, bridged ring system containing 2 ring N heteroatoms, and wherein R 1  is optionally substituted with 1 R 4 , optionally R 1  is a 7- to 8-membered saturated, bridged ring containing 2 ring N heteroatoms, wherein at least 1 ring N heteroatom is not at the point of attachment of R 1 , and wherein R 1  is optionally substituted with 1 R 4 . 
     
     
         31 . The compound, or a pharmaceutically acceptable salt or derivative thereof, of any of  claims 13-30 , wherein the bicyclic heteroaromatic ring system containing X 1 , X 2 , Y 1 , Y 2 , Z 1 , Z 2  and Z 3  is selected from: 
       
         
           
           
               
               
           
         
       
     
     
         32 . A compound selected from:
 (S)—N-(chroman-4-yl)-2-(4-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide;   (S)—N-(chroman-4-yl)-2-(6-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide;   (S)—N-(chroman-4-yl)-2-(2-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide;   (S)—N-(chroman-4-yl)-2-(5-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide;   (R)-2-(pyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-benzo[d]imidazole-5-carboxamide;   (S)-2-(pyridin-3-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-benzo[d]imidazole-5-carboxamide;   (R)—N-(chroman-4-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide;   (S)—N-(chroman-4-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide;   (R)—N-(2,3-dihydro-1H-inden-1-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide;   (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide;   (R)—N-(6-chlorochroman-4-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide;   (S)—N-(6-chlorochroman-4-yl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide;   (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxamide;   (R)-2-(1-methylpiperidin-4-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-benzo[d]imidazole-5-carboxamide;   (S)-2-(1-methylpiperidin-4-yl)-N-(1,2,3,4-tetrahydronaphthalen-1-yl)-1H-benzo[d]imidazole-5-carboxamide;   (R)—N-(6-chlorochroman-4-yl)-2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxamide;   (S)—N-(6-chlorochroman-4-yl)-2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxamide;   (S)—N-(chroman-4-yl)-2-(1-methylpiperidin-4-yl)-1H-benzo[d]imidazole-5-carboxamide;   (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-1H-benzo[d]imidazole-5-carboxamide;   (S)—N-(chroman-4-yl)-1-methyl-2-(4-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide;   (S)—N-(chroman-4-yl)-1-methyl-2-(6-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide;   (S)—N-(chroman-4-yl)-1-methyl-2-(2-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide;   (S)—N-(chroman-4-yl)-1-methyl-2-(5-methylpyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide;   (S)—N-(chroman-4-yl)-1-methyl-2-(pyridin-3-yl)-1H-benzo[d]imidazole-5-carboxamide;   (S)—N-(chroman-4-yl)-1-methyl-2-(4-methylpyridin-3-yl)-1H-benzo[d]imidazole-6-carboxamide;   (S)—N-(chroman-4-yl)-1-methyl-2-(6-methylpyridin-3-yl)-1H-benzo[d]imidazole-6-carboxamide;   (S)—N-(chroman-4-yl)-1-methyl-2-(2-methylpyridin-3-yl)-1H-benzo[d]imidazole-6-carboxamide;   (S)—N-(chroman-4-yl)-1-methyl-2-(5-methylpyridin-3-yl)-1H-benzo[d]imidazole-6-carboxamide;   (S)—N-(chroman-4-yl)-1-methyl-2-(pyridin-3-yl)-1H-benzo[d]imidazole-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-1-methyl-1H-benzo[d]imidazole-6-carboxamide;   (S)—N-(chroman-4-yl)-1-methyl-2-(piperazin-1-yl)-1H-benzo[d]imidazole-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-1-methyl-1H-benzo[d]imidazole-5-carboxamide;   (S)—N-(chroman-4-yl)-1-methyl-2-(piperazin-1-yl)-1H-benzo[d]imidazole-5-carboxamide;   (S)—N-(chroman-4-yl)-2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(6-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(5-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(4-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(2-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(2,6-dimethylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(4-methylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-morpholino-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide;   (S)-2-(4-(tert-butyl)piperazin-1-yl)-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(4-isopropylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide;   (R)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide;   (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(piperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(1-methylpiperidin-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-[1,2,4]triazolo[1, 5-a]pyridine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(2-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide;   (S)—N-(chroman-4-yl)-2-(4-methylpyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide;   (S)—N-(chroman-4-yl)-2-(4-hydroxypiperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide;   (S)—N-(chroman-4-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide;   (S)—N-(chroman-4-yl)-2-(4-methylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide;   (S)—N-(chroman-4-yl)-2-morpholino-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide;   (S)-2-(4-(tert-butyl)piperazin-1-yl)-N-(chroman-4-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide;   (S)—N-(chroman-4-yl)-2-(piperidin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide;   (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide;   (S)—N-(chroman-4-yl)-2-(4-isopropylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide;   (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide;   (R)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide;   (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(4-methylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide;   (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(4-ethylpiperazin-1-yl)-[1,2,4]triazolo[1,5-a]pyridine-7-carboxamide;   2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)imidazo[1,2-a]pyridine-6-carboxamide;   2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylimidazo[1,2-a]pyridine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   N-cyclopentyl-2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   N-cyclohexyl-2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   N-(4,4-difluorocyclohexyl)-2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(4-ethylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   N-cyclopentyl-2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   N-cyclohexyl-2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   N-(4,4-difluorocyclohexyl)-2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(4-methylpiperazin-1-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylpyrazolo[1,5-a]pyrimidine-6-carboxamide;   N-cyclopentyl-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   (S)—N-(2,3-dihydro-1H-inden-1-yl)-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   N-cyclopentyl-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   N-cyclohexyl-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   N-(4,4-difluorocyclohexyl)-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   N-(4-fluorobenzyl)-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(pyridin-3-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   N-(4,4-difluorocyclohexyl)-7-methyl-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   (S)—N-(chroman-4-yl)-7-methyl-2-(piperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(1-ethylpiperidin-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide;   N-(4,4-difluorocyclohexyl)-2-(1-ethylpiperidin-4-yl)-7-methylpyrazolo[1,5-a]pyrimidine-6-carboxamide;   (S)—N-(chroman-4-yl)-7-methyl-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   N-(4,4-difluorocyclohexyl)-7-methyl-2-(1-methylpiperidin-4-yl)pyrazolo[1,5-a]pyrimidine-6-carboxamide;   N-cyclopentyl-2-(piperidin-4-yl)benzo[d]oxazole-5-carboxamide;   N-cyclopentyl-2-(1-methylpiperidin-4-yl)benzo[d]oxazole-5-carboxamide;   N-cyclopentyl-2-(1-ethylpiperidin-4-yl)benzo[d]oxazole-5-carboxamide;   (S)—N-(chroman-4-yl)-2-(piperazin-1-yl)benzo[d]oxazole-5-carboxamide;   N-cyclopentyl-2-(piperazin-1-yl)benzo[d]oxazole-5-carboxamide;   (S)—N-(chroman-4-yl)-2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-5-carboxamide;   N-cyclopentyl-2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-5-carboxamide;   (S)—N-(chroman-4-yl)-2-(4-methylpiperazin-1-yl)benzo[d]oxazole-5-carboxamide;   N-cyclopentyl-2-(4-methylpiperazin-1-yl)benzo[d]oxazole-5-carboxamide;   (S)—N-(chroman-4-yl)-2-(4-(2-hydroxyethyl)piperazin-1-yl)benzo[d]oxazole-5-carboxamide;   N-cyclopentyl-2-(4-(2-hydroxyethyl)piperazin-1-yl)benzo[d]oxazole-5-carboxamide;   N-cyclopentyl-2-(4-ethylpiperazin-1-yl)benzo[d]oxazole-6-carboxamide;   N-cyclopentyl-2-(piperazin-1-yl)benzo[d]oxazole-6-carboxamide;   (S)—N-(chroman-4-yl)-2-(1-methyl-1H-pyrazol-4-yl)benzo[d]oxazole-6-carboxamide;   N-cyclopentyl-2-(piperidin-4-yl)thiazolo[5,4-b]pyridine-5-carboxamide;   N-(4,4-difluorocyclohexyl)-2-(piperidin-4-yl)thiazolo[5,4-b]pyridine-5-carboxamide;   N-cyclopentyl-2-(1-methylpiperidin-4-yl)thiazolo[5,4-b]pyridine-5-carboxamide;   N-(4,4-difluorocyclohexyl)-2-(1-methylpiperidin-4-yl)thiazolo[5,4-b]pyridine-5-carboxamide;   2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylthiazolo[5,4-b]pyridine-5-carboxamide;   2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)thiazolo[5,4-b]pyridine-5-carboxamide;   2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)thiazolo[4,5-b]pyridine-6-carboxamide;   N-cyclopentyl-2-(piperidin-4-yl)thiazolo[4,5-b]pyridine-6-carboxamide;   2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylthiazolo[4,5-c]pyridine-6-carboxamide;   2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)thiazolo[4,5-c]pyridine-6-carboxamide;   2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-cyclopentylthieno[3,2-b]pyridine-6-carboxamide;   2-(3,8-diazabicyclo[3.2.1]octan-8-yl)-N-(4,4-difluorocyclohexyl)thieno[3,2-b]pyridine-6-carboxamide;   or a pharmaceutically acceptable salt or derivative thereof.   
     
     
         33 . A pharmaceutical composition comprising a compound or a pharmaceutically acceptable salt or derivative as defined in any of  claims 1-32 , and a pharmaceutically acceptable excipient. 
     
     
         34 . A compound or pharmaceutically acceptable salt or derivative of any of  claims 13-32  for use in therapy. 
     
     
         35 . A compound or pharmaceutically acceptable salt or derivative of any of  claims 13-32  or a pharmaceutical composition of  claim 33  for use in the treatment or prevention of a disease or disorder that can be ameliorated by activation of long isoforms of PDE4 or a disease or disorder mediated by excessive intracellular cyclic AMP signalling. 
     
     
         36 . The compound or pharmaceutically acceptable salt or derivative for use of any of  claims 1 to 12  or the compound or pharmaceutically acceptable salt or derivative or pharmaceutical composition for use of  claim 35  in the treatment or prevention of a disease or disorder mediated by excessive intracellular cyclic AMP signalling. 
     
     
         37 . The compound or pharmaceutically acceptable salt or derivative or pharmaceutical composition for use of  claim 36  wherein the excessive intracellular cyclic AMP signalling is caused by:
 a. excessive hormone levels produced by an adenoma. 
 b. a gain-of-function gene mutation in a G-protein coupled receptor (GPCR); 
 c. an activating mutation in the GNAS1 gene, which encodes the α-subunit of the G-protein G s ; or 
 d. a bacterial toxin. 
 
     
     
         38 . The compound or pharmaceutically acceptable salt or derivative or pharmaceutical composition for use of any of  claims 1-12 or 34-37 , wherein the disease is cancer. 
     
     
         39 . The compound or pharmaceutically acceptable salt or derivative or pharmaceutical composition for use of  claim 38 , wherein the cancer is prostate cancer. 
     
     
         40 . The compound or pharmaceutically acceptable salt or derivative or pharmaceutical composition for use of any of  claims 1-12 or 34-37 , wherein the disease is:
 a. pituitary adenoma, Cushing's disease, polycystic kidney disease or polycystic liver disease;   b. hyperthyroidism, Jansens's metaphyseal chondrodysplasia, hyperparathyroidism, or familial male-limited precocious puberty;   c. McCune-Albright syndrome;   d. cholera, whooping cough, anthrax, or tuberculosis;   e. HIV, AIDS, or Common Variable Immunodeficiency (CVID);   f. melanoma, pancreatic cancer, leukaemia, prostate cancer, adrenocortical tumours, testicular cancer, primary pigmented nodular adrenocortical diseases (PPNAD), or Carney Complex;   g. autosomal dominant polycystic kidney disease (ADPKD) or autosomal recessive polycystic kidney disease (ARPKD); or   h. maturity onset diabetes of young type 5 (MODY5); or   i. cardiac hypertrophy.   
     
     
         41 . The compound or pharmaceutically acceptable salt or derivative or pharmaceutical composition for use of  claim 40 , wherein the disease is:
 a. autosomal dominant polycystic kidney disease (ADPKD); or   b. autosomal recessive polycystic kidney disease (ARPKD).   
     
     
         42 . The compound or pharmaceutically acceptable salt or derivative or pharmaceutical composition for use of  claim 40 , wherein the disease is hyperparathyroidism.